The proposed studies involve clinical and laboratory investigations in adult patient with primary hypercholesterolemia on the basis of two disorders, heteroxygous familial hypercholesterolemia (FH) and combined familial hyperlipidemia (CFH). The pathophysiology of hypercholesterolemia in these two disorders differs (decreased LDL receptor activity and a reduced FCR of LDL in FH vs. an increased synthesis of VLDL and LDL in CFH) but whether or not this influences the hypolipidemic effects of bile acid sequestrants or nicotinic acid is not known. We plan to undertake steady-state metabolic studies in patients with FH and CFH during sequential therapy with: a) a low cholesterol, fat restricted diet, b) diet + colestipol, c) diet + nicotinic acid and (in patients with FH) diet + colestipol + nicotonic acid. These studies will simultaneously examine three interrelated parameters: 1) the turnover of 125I-LDL, 2) whole body cholesterol synthesis assessed by sterol balance techniques and 3) LDL receptor activity, cholesterol synthesis, and cholesterol ester hydrolase activity on freshly-isolated mononuclear cells. These parameters will be correlated with changes in the concentrations of individual lipoproteins, apoproteins A1, B, CIII, and E, LDL composition and the maximum number of LDL receptors on derepressed lymphocytes. In addition, the metabolism of 125I-LDL will be examined under non-steady state conditions during the first 8 days of colestipol therapy to assess whether or not the initial hypolipidemic effects differ from those seen in the steady state situation. We also plan to seed metabolic explanations for the heterogeneity in response to colestipol seen in patients with FH. Metabolic studies will be undertaken in two groups of patients designated as good vs. poor responders on the basis of their hypolipidemic response to colestipol. Overall, these studies should provide new information in several areas including: 1) comparative aspects of hypolipidemic therapy in patients with FH vs. CFH, 2) the extent to which changes in lipid metabolism in freshly-isolated mononuclear cells may parallel those which occur in the whole body, 3) the mechanisms responsible for the hypolipidemic effects of combined colestipol + nicotinic acid therapy in patients with FH.